The Rapoport-Luebering Pathway

1. The Rapoport-Luebering Pathway Dr. Sooad Al-Daihan Biochemistry department

2. Overview • In RBCs, glycolysis is modified by the Rapoport-Luebering shunt. • It is a biochemical pathway in mature erythrocytes involving the formation of 2,3-bisphosphoglycerate and which regulates oxygen release from hemoglobin and delivery to tissues. Hence, the name “ 2,3- bisphosphglycerate (2,3-BPG) shunt.

3. The Pathway • There are 2 steps in this shunt: • Bisphosphoglyceratemutase converts 1,3-BPG in to 2,3-BPG. • 2,3-BPG is hydrolysed to 3-phosphoglycerate by 2,3-bisphosphoglycerate phosphatase. • ATP Yield: Mature RBCs contain no mitochondria, thus they depend only upon glycolysis for energy production 2 ATP.

4. Role of 2,3-BPG in haemoglobin function • 2,3 BPG acts as an allosteric regulator of hemoglobin that has the ability to decrease the affinity of O2 to hemoglobin, . • When a hemoglobin molecule is O2 deficient, 2,3 BPG inserts itself between the two beta chains, where it contains positively charged amino acids that form salt bridges with the negatively charged phosphate groups of 2,3-BPG. • The lower affinity for O2 means that the hemoglobin’s delivery of O2 to the tissues is enhanced when needed.

5. Sorbitol Metabolism(polyol pathway)

6. Sorbitol • Sorbitol, a polyol , is a bulk sweetener found in numerous food products. • In addition to providing sweetness, it is an excellent humectant and texturizing agent.

7. It is a sugar alcohol that the human body metabolizes slowly. • It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group by the action of aldose reductase. • It is broken down by the action of sorbitol dehydrogenase, which oxidizes sorbitol to fructose. • In the liver, this provides a way for dietary sorbitol enter glycolysis or gluconeogenesis and be metabolized further.

8. Complication of increased sorbitol • At high glucose levels, aldose reductase activity occurs in tissues which often lack sorbitol dehydrogenase This leads to an accumulation of sorbitol in these tissues. • For example in the lens of the eye, leading to cataractformation due to osmotic damage.

9. Ethanol Catabolism

10. Catabolism of Ethanol • Ethanol cannot be excreted and must be metabolized, primarily by the liver. • This metabolism occurs by two pathways. • The first pathway comprises two steps: • The first step, catalyzed by the enzyme alcohol dehydrogenase, takes place in the cytoplasm • The second step, catalyzed by aldehyde dehydrogenase, takes place in mitochondria. • The second pathway for ethanol metabolism is called the ethanol inducible microsomal ethanol-oxidizing system (MEOS). • This cytochrome P450-dependent pathway generates acetaldehyde and subsequently acetate while oxidizing biosynthetic reducing power, NADPH, to NADP+.

11. Metabolic effect of ethanol: • The fate of acetate depends on the ratio of NADH to NAD+. • Both alcohol dehydrogenase and aldehyde dehydrogenase consume NAD+, contributing to a high NADH:NAD+, resulting in: • Inhibition of the citric acid cycle, because NADH inhibits two important regulatory enzymes: isocitrate dehydrogenase and α-ketoglutarate dehydrogenase • Inhibition of gluconeogenesis by preventing the oxidation of lactate to pyruvate. In fact, the high concentration of NADH will cause the reverse reaction to predominate, and lactate will accumulate. The consequences may be hypoglycemia and lactic acidosis